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,
*
Mycobacteria Research Laboratories, Department of Microbiology, Colorado State University, Fort Collins, CO 80523;
Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Health Sciences Center, Boulder, CO 80206; and
Department of Medicine, National Jewish Medical and Research Center, Denver, CO 80262
Of the two common morphotypes of Mycobacterium
avium, designated smooth transparent (SmT) or smooth opaque
(SmO), the SmO morphotype is avirulent, whereas the SmT morphotype is
virulent. The role of the host macrophage in determining these
different virulence phenotypes was analyzed using an in vitro model of
macrophage infection. Initial studies confirmed previous reports of the
increased ability of the SmT bacteria to grow in macrophages; this
increased virulence correlated with reduced induction of inflammatory
cytokines. Examination of the response of the mitogen-activated protein
kinase (MAPK) pathway following infection with either morphotype
revealed that all three members of the MAPK pathway were activated.
Pharmacologic inhibition of either the extracellular signal-regulated
kinase (ERK) or p38MAPK pathways resulted in
distinct consequences for the growth of the two morphotypes. In
particular, inhibition of the p38MAPK resulted
in attenuated growth of the SmT morphotype, which correlated with
reduced PGE2 production. Inhibition of cyclooxygenase 2 by
indomethacin also inhibited growth of SmT, substantiating the role for
PGE2 in promoting the growth of SmT. In contrast, SmO
induction of the ERK pathway was increased compared with the SmT
morphotype, and inhibition of ERK resulted in decreased TNF-
synthesis and enhanced SmO growth. Pharmacologic inhibitors of the MAPK
pathway were present for only the first 4 h of infection and yet
had consequences for bacterial growth at 7 days. Therefore, the data
suggest that induction of the MAPK pathway during uptake of bacteria is
instrumental in determining the eventual fate of the
bacteria.
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